Name: synthesis of 68ga core-doped iron oxide nanoparticles for dual positron emission tomography /(t1)magnetic resonance imaging
Uploaded: 2018-11-20T13:00:00
Description: Watch this Scientific Journal Video about Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /T1Magnetic Resonance Imaging at JoVE.com

This study was supported by a grant from the Spanish Ministry for Economy and Competitiveness (MEyC) (grant number: SAF2016-79593-P) and from the Carlos III Health Research Institute (grant number: DTS16/00059). The CNIC is supported by the Ministerio de Ciencia, Innovaci&#243;n y Universidades) and the Pro CNIC Foundation and is a Severo Ochoa Centre of Excellence (MEIC award SEV-2015-0505).

1. Reagent Preparation
<ol>
	<li>0.05 M HCl
	<ol>
		<li>Prepare 0.05 M HCl by adding 208 &#181;L of 37% HCl to 50 mL of distilled water.</li>
	</ol>
	</li>
	<li>High-performance liquid chromatography eluent
	<ol>
		<li>Prepare high-performance liquid chromatography (HPLC) eluent by dissolving 6.9 g of sodium dihydrogen phosphate monohydrate, 7.1 g of disodium hydrogen phosphate, 8.7 g of sodium chloride, and 0.7 g of sodium azide in 1 L of water. Mix well and check the pH. Pass the elu...

<ol>
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(24), 3511-3524 (2009).</li><li>Lee, S., Chen, X. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dual-modality+probes+for+in+vivo+molecular+imaging.">Dual-modality probes for in vivo molecular imaging.</a> Molecular Imaging. 8 (2), 87-100 (2009).</li><li>Louie, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Multimodality+Imaging+Probes:+Design+and+Challenges.">Multimodality Imaging Probes: Design and Challenges.</a> Chemical Reviews. 110 (5), 3146-3195 (2010).</li><li>Judenhofer, M. 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K., Allard, M., Fernandez, P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gallium-68:+chemistry+and+radiolabeled+peptides+exploring+different+oncogenic+pathways.">Gallium-68: chemistry and radiolabeled peptides exploring different oncogenic pathways.</a> Cancer Biotherapy &amp; Radiopharmaceuticals. 28 (2), 85-97 (2013).</li><li>Moon, S. -. H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+complementary+PET/MR+dual-modal+imaging+probe+for+targeting+prostate-specific+membrane+antigen+(PSMA).">Development of a complementary PET/MR dual-modal imaging probe for targeting prostate-specific membrane antigen (PSMA).</a> Nanomedicine: Nanotechnology, Biology and Medicine. 12 (4), 871-879 (2016).</li><li>Kim, S. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hybrid+PET/MR+imaging+of+tumors+using+an+oleanolic+acid-conjugated+nanoparticle.">Hybrid PET/MR imaging of tumors using an oleanolic acid-conjugated nanoparticle.</a> Biomaterials. 34 (33), 8114-8121 (2013).</li><li>Yang, B. Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+of+a+multimodal+imaging+probe+by+encapsulating+iron+oxide+nanoparticles+with+functionalized+amphiphiles+for+lymph+node+imaging.">Development of a multimodal imaging probe by encapsulating iron oxide nanoparticles with functionalized amphiphiles for lymph node imaging.</a> Nanomedicine. 10 (12), 1899-1910 (2015).</li><li>Comes Franchini, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Biocompatible+nanocomposite+for+PET/MRI+hybrid+imaging.">Biocompatible nanocomposite for PET/MRI hybrid imaging.</a> International Journal of Nanomedicine. 7, 6021 (2012).</li><li>Karageorgou, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Gallium-68+Labeled+Iron+Oxide+Nanoparticles+Coated+with+2,3-Dicarboxypropane-1,1-diphosphonic+Acid+as+a+Potential+PET/MR+Imaging+Agent:+A+Proof-of-Concept+Study.">Gallium-68 Labeled Iron Oxide Nanoparticles Coated with 2,3-Dicarboxypropane-1,1-diphosphonic Acid as a Potential PET/MR Imaging Agent: A Proof-of-Concept Study.</a> Contrast Media &amp; Molecular Imaging. 2017, 1-13 (2017).</li><li>Madru, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=(68)Ga-labeled+superparamagnetic+iron+oxide+nanoparticles+(SPIONs)+for+multi-modality+PET/MR/Cherenkov+luminescence+imaging+of+sentinel+lymph+nodes.">(68)Ga-labeled superparamagnetic iron oxide nanoparticles (SPIONs) for multi-modality PET/MR/Cherenkov luminescence imaging of sentinel lymph nodes.</a> American Journal of Nuclear Medicine and Molecular Imaging. 4 (1), 60-69 (2013).</li><li>Lahooti, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=PEGylated+superparamagnetic+iron+oxide+nanoparticles+labeled+with+68Ga+as+a+PET/MRI+contrast+agent:+a+biodistribution+study.">PEGylated superparamagnetic iron oxide nanoparticles labeled with 68Ga as a PET/MRI contrast agent: a biodistribution study.</a> Journal of Radioanalytical and Nuclear Chemistry. 311 (1), 769-774 (2017).</li><li>Lee, H. -. Y., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=PET/MRI+dual-modality+tumor+imaging+using+arginine-glycine-aspartic+(RGD)-conjugated+radiolabeled+iron+oxide+nanoparticles.">PET/MRI dual-modality tumor imaging using arginine-glycine-aspartic (RGD)-conjugated radiolabeled iron oxide nanoparticles.</a> Journal of Nuclear Medicine. 49 (8), 1371-1379 (2008).</li><li>Patel, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+cell+labeling+efficacy,+cytotoxicity+and+relaxivity+of+copper-activated+MRI/PET+imaging+contrast+agents.">The cell labeling efficacy, cytotoxicity and relaxivity of copper-activated MRI/PET imaging contrast agents.</a> Biomaterials. 32 (4), 1167-1176 (2011).</li><li>Choi, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+Hybrid+Nanoparticle+Probe+for+Dual-Modality+Positron+Emission+Tomography+and+Magnetic+Resonance+Imaging.">A Hybrid Nanoparticle Probe for Dual-Modality Positron Emission Tomography and Magnetic Resonance Imaging.</a> Angewandte Chemie International Edition. 47 (33), 6259-6262 (2008).</li><li>Wong, R. M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapid+size-controlled+synthesis+of+dextran-coated,+64Cu-doped+iron+oxide+nanoparticles.">Rapid size-controlled synthesis of dextran-coated, 64Cu-doped iron oxide nanoparticles.</a> ACS Nano. 6 (4), 3461-3467 (2012).</li><li>Osborne, E. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapid+microwave-assisted+synthesis+of+dextran-coated+iron+oxide+nanoparticles+for+magnetic+resonance+imaging.">Rapid microwave-assisted synthesis of dextran-coated iron oxide nanoparticles for magnetic resonance imaging.</a> Nanotechnology. 23 (21), 215602 (2012).</li><li>Pellico, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fast+synthesis+and+bioconjugation+of+68+Ga+core-doped+extremely+small+iron+oxide+nanoparticles+for+PET/MR+imaging.">Fast synthesis and bioconjugation of 68 Ga core-doped extremely small iron oxide nanoparticles for PET/MR imaging.</a> Contrast Media &amp; Molecular Imaging. 11 (3), 203-210 (2016).</li><li>Pellico, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=In+vivo+imaging+of+lung+inflammation+with+neutrophil-specific+68Ga+nano-radiotracer.">In vivo imaging of lung inflammation with neutrophil-specific 68Ga nano-radiotracer.</a> Scientific Reports. 7 (1), 13242 (2017).</li></ol>

Iron oxide nanoparticles are a well-established contrast agent for T2-weighted MRI. However, due to the drawbacks of this type of contrast for the diagnosis of certain pathologies, T1-weighted or bright contrast is many times preferred. The nanoparticles presented here not only overcome these limitations by offering positive contrast in MRI but also offer a signal in a functional imaging technique, such as PET, via 68Ga incorporation in their core. Microwave technology enhances t...

The combination of imaging techniques for medical purposes has triggered the quest for different methods to synthesize multimodal probes1,2,3. Due to the sensitivity of positron emission tomography (PET) scanners and the spatial resolution of MRI, PET/MRI combinations seem to be one of the most attractive possibilities, providing anatomical and functional information at the same time4. In MRI, T2-weighted sequences can be used, darkening the tissues in which they accumulate. T1-weighted sequences may also be used, producing the brightening of the specific accumulation location5. Among them, positive contrast is often the most adequate option, as negative contrast makes it much harder to differentiate signal from endogenous hypointense areas, including those often presented by organs such as the lungs6. Traditionally, Gd-based molecular probes have been employed to obtain positive contrast. However, Gd-based contrast agents present a major drawback, namely their toxicity, which is critical in patients with renal problems7,8,9. This has motivated research in the synthesis of biocompatible materials for their use as T1 contrast agents. An interesting approach is the use of iron oxide nanoparticles (IONPs), with an extremely small core size, that provide positive contrast10. Due to this extremely small core (~2 nm), most of the Fe3+ ions are on the surface, with 5 unpaired electrons each. This increases longitudinal relaxation time (r1) values and yields much lower transversal/longitudinal (r2/r1) ratios compared to traditional IONPs, producing the desired positive contrast11.
To combine IONPs with a positron emitter for PET, there are two key issues to take into account: radioisotope election and nanoparticle radiolabeling. Regarding the first issue, 68Ga is an alluring choice. It has a relatively short half-life (67.8 min). Its half-life is suitable for peptide labeling since it matches common peptide biodistribution times. Moreover, 68Ga is produced in a generator, enabling the synthesis in bench modules and avoiding the need for a cyclotron nearby12,13,14. In order to radiolabel the nanoparticle, surface-labeling radioisotope incorporation is the prevalent strategy. This can be done using a ligand that chelates 68Ga or taking advantage of the affinity of the radiometal toward the surface of the nanoparticle. Most examples in the literature concerning IONPs use a chelator. There are examples of the use of heterocyclic ligands such as 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)15, 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA)16,17, and 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA)18, and the use of 2,3-dicarboxypropane-1,1-diphosphonic acid (DPD), a tetradentate ligand 19. Madru et al.20 developed a chelator-free strategy in 2014 to label IONPs using a chelator-free method used by another group posteriorly21.
However, major drawbacks of this approach include a high risk of in vivo transmetalation, low radiolabeling yields, and lengthy protocols unsuitable for short-lived isotopes22,23,24. For this reason, Wong et al.25 developed the first example of core-doped nanoparticles, managing to incorporate 64Cu in the core of the IONPs in a 5-min synthesis using microwave technology.
Here, we describe a rapid and efficient procedure to incorporate the radionuclide into the core of the nanoparticle, eluding many of the drawbacks presented by traditional methods. For this purpose, we propose the use of a microwave-driven synthesis (MWS), which reduces reaction times considerably, increases yields, and enhances reproducibility, critically important parameters in IONP synthesis. The refined performance of MWS is due to dielectric heating: rapid sample heating as molecular dipoles try to align with the alternating electric field, being polar solvents and reagents more efficient for this type of synthesis. In addition, the use of citric acid as a surfactant, together with microwave technology, results in extremely small nanoparticles, producing a dual T1-weighted MRI/PET26 signal, herein denoted as 68Ga Core-doped iron oxide nanoparticles (68Ga-C-IONP).
The protocol combines the use of microwave technology, 68GaCl3 as positron emitter, iron chloride, sodium citrate, and hydrazine hydrate, resulting in dual T1-weighted MRI/PET nanoparticulate material in hardly 20 min. Moreover, it yields consistent results over a range of 68Ga activities (37 MBq, 111 MBq, 370 MBq, and 1110 MBq) with no significant effects on the main physicochemical properties of the nanoparticles. The reproducibility of the method using high 68Ga activities extends the field of possible applications, including large animal models or human studies. In addition, there is a single purification step included in the method. In the process, any excess of free gallium, iron chloride, sodium citrate, and hydrazine hydrate are removed by gel filtration. Total free isotope elimination and the purity of the sample ensure no toxicity and enhance imaging resolution. In the past, we have already demonstrated the usefulness of this approach in targeted molecular imaging27,28.

<table>
	<tbody>
		<tr>
			<td>Iron (III) chloride hexahydrate</td>
			<td>POCH</td>
			<td>2317294</td>
			<td></td>
		</tr>
		<tr>
			<td>Citric acid, trisodium salt dihydrate 99%</td>
			<td>Acros organics</td>
			<td>227130010</td>
			<td></td>
		</tr>
		<tr>
			<td>Hydrazine hydrate</td>
			<td>Aldrich</td>
			<td>225819</td>
			<td></td>
		</tr>
		<tr>
			<td>Hydrochloric acid 37%</td>
			<td>Fisher Scientific</td>
			<td>10000180</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium dihydrogen phosphate monohydrate</td>
			<td>Aldrich</td>
			<td>S9638</td>
			<td></td>
		</tr>
		<tr>
			<td>Disodium phosphate dibasic</td>
			<td>Aldrich</td>
			<td>S7907</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium chloride</td>
			<td>Aldrich</td>
			<td>746398</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium Azide</td>
			<td>Aldrich</td>
			<td>S2002</td>
			<td></td>
		</tr>
		<tr>
			<td>Sodium dihydrogen phosphate anhydrous</td>
			<td>POCH</td>
			<td>799200119</td>
			<td></td>
		</tr>
		<tr>
			<td>68Ga Chloride</td>
			<td>&#160;ITG Isotope Technologies Garching GmbH, Germany</td>
			<td>68Ge/68Ga generator system</td>
			<td></td>
		</tr>
		<tr>
			<td>Microwave</td>
			<td>Anton Paar</td>
			<td>Monowave 300</td>
			<td></td>
		</tr>
		<tr>
			<td>Centrifuge</td>
			<td>Hettich</td>
			<td>Universal 320</td>
			<td></td>
		</tr>
		<tr>
			<td>Size Exclusion columns</td>
			<td>GE Healthcare</td>
			<td>PD-10</td>
			<td></td>
		</tr>
	</tbody>
</table>

synthesis of 68ga core-doped iron oxide nanoparticles for dual positron emission tomography /(t1)magnetic resonance imaging

Here, we describe a microwave synthesis to obtain iron oxide nanoparticles core-doped with 68Ga. Microwave technology enables fast and reproducible synthetic procedures. In this case, starting from FeCl3 and citrate trisodium salt, iron oxide nanoparticles coated with citric acid are obtained in 10 min in the microwave. These nanoparticles present a small core size of 4.2 &#177; 1.1 nm and a hydrodynamic size of 7.5 &#177; 2.1 nm. Moreover, they have a high longitudinal relaxivity (r1) value of 11.9 mM-1&#183;s-1 and a modest transversal relaxivity value (r2) of 22.9 mM-1&#183;s-1, which results in a low r2/r1 ratio of 1.9. These values enable positive contrast generation in magnetic resonance imaging (MRI) instead of negative contrast, commonly used with iron oxide nanoparticles. In addition, if a 68GaCl3 elution from a 68Ge/68Ga generator is added to the starting materials, a nano-radiotracer doped with 68Ga is obtained. The product is obtained with a high radiolabeling yield (&#62; 90%), regardless of the initial activity used. Furthermore, a single purification step renders the nano-radiomaterial ready to be used in vivo.

68Ga-C-IONP were synthesized by combining FeCl3, 68GaCl3, citric acid, water, and hydrazine hydrate. This mixture was introduced into the microwave for 10 min at 120 &#176;C and 240 W under controlled pressure. Once the sample had cooled down to room temperature, the nanoparticles were purified by gel filtration to eliminate unreacted species (FeCl3, citrate, hydrazine hydrate) and free 68Ga (Figure 1</...

Watch this Scientific Journal Video about Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /T1Magnetic Resonance Imaging at JoVE.com

Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /T1Magnetic Resonance Imaging

Here, we present a protocol to obtain 68Ga core-doped iron oxide nanoparticles via fast microwave-driven synthesis. The methodology renders PET/(T1)MRI nanoparticles with radiolabeling efficiencies higher than 90% and radiochemical purity of 99% in a 20-min synthesis.

Synthesis of 68Ga Core-doped Iron Oxide Nanoparticles for Dual Positron Emission Tomography /(T1)Magnetic Resonance Imaging

Here, we describe a microwave synthesis to obtain iron oxide nanoparticles core-doped with 68Ga. Microwave technology enables fast and reproducible ...

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